Coronary vascular occlusion can lead to myocardial infarction with subsequent loss of myocardial cells, and eventual scar formation. The consequence is loss of muscular function that can lead to congestive heart failure and possibly, death. Numerous attempts have been made to regenerate cardiac vessels and the myocardium. It has been demonstrated that bone marrow-derived stem cells migrate to the injured myocardium and then differentiate into both endothelial and myocardial cells, with partial restoration of cardiac function. We and others have shown that mesenchymal stem cells (MSCs) may participate in cardiac repair after intra-myocardial injection. Based on the hypothesis that specific signals are responsible for the homing and adherence of MSCs to myocardium and subsequent engraftment in the myocardium, we propose to study the following specific aims: 1) to optimize the conditions for isolation of MSCs that have capacity to differentiate into cardiac myocytes, and to further characterize these MSCs 2) to determine the chemical signals and adhesion receptors that mediate homing of MSCs to ischemic myocardium; 3) to further enrich for the sub-set of MSCs that expresses receptors/ligands that mediate specific myocardial homing and to genetically modify these MSCs so as to enhance homing and adhesion to the ischemic myocardium, 4) to determine whether systemic delivery of enriched and/or modified MSCs is a superior strategy to systemic delivery, or direct intra-myocardial delivery of non-modified MSCs for purposes of cardiac regeneration and recovery of cardiac function. Since the phenotype of MSCs that differentiate into cardiac myocytes is uncertain, we plan to optimize conditions for the isolation of MSCs that differentiate into cardiac myocytes, and to further characterize the "signature" of this sub-population of MSCs. Using genomics and proteomics, we will then screen which cytokines and adhesion receptors are upregulated in the ischemic myocardium, and whether these cytokines can be used to enhance trafficking and homing of MSCs to the myocardium. Having identified cytokines and adhesion receptors integral to the homing and engraftment process, we will perform genetic manipulations on MSCs (for example, to over express cytokine receptors or specific adhesion ligands) and determine whether this strategy will enhance viability, homing and engraftment of MSCs to the ischemic myocardium. Finally, we will examine if systemic administration of genetically modified MSCs is a superior therapeutic strategy to direct intramyocardial injection for cardiac repair and regeneration. Such specific manipulations to enhance the process of homing and engraftment to the myocardium will improve therapeutic options for ischemic heart disease and congestive heart failure.